The mechanism of leukocyte chemotaxis is being studied as a model for signa transduction by a G-protein coupled receptor. Studies in this laboratory have demonstrated a role for a methylation reaction in leukocyte chemotaxis and in other important biological responses. Protein carboxyl methylation is being studied as a posttranslational modification found in a number of membrane proteins possibly involved in signal transduction. A. A role for the G-protein Gi-2 in the chemotaxis of macrophage and neutrophils has been demonstrated by this and other laboratories. The role of methylation in membrane attachment and function of G-proteins was studied. We have demonstrated carboxyl methylation and processing of the G protein gamma-subunit in brain. The G-protein gamma-subunit contains a C- terminal Cys-Axx-Axx-Xxx sequence, which is modified by a multi-step proces including isoprenylation and methylation. We have demonstrated that isoprenylation by itself was not sufficient for membrane attachment of an otherwise soluble protein. B. We have identified a GTP-dependent carboxyl methylation of several low- molecular weight GTP-binding proteins. One of the methylated proteins in brain was identified as G25K, and additional methylated proteins were observed in a macrophage cell line. The properties of the reaction indicat that methylation may regulate the association of these proteins with the membrane. By altering the localization of these proteins, methylation may act as a molecular switch to regulate transduction of specific biochemical signals. Carboxyl methylation may provide a novel target for pharmacologic manipulation of a variety of cell signaling systems controlling cell growth motility, neurotransmitter release, and cell-cell interactions.